Throughout this application, various references are cited in square brackets to describe more fully the state of the art to which this invention pertains. The disclosure of these references is hereby incorporated by reference into the present disclosure.
The best way to prime CD8+ CTL is to synthesize the target antigens by DNA transfection or infection using viral or bacterial vectors. The requirements as viral vaccine vectors are a broad range of hosts and good expression of gene of interests. Vesicular stomatitis virus (VSV) infects most mammalian cells and expresses viral proteins up to 60% of total proteins in infected cells [Kim, G. N., and C. Y. Kang. Virology 357:41, 2007]. In nature VSV infects pigs, cattle, and horses, and causes vesicular disease around the mouth and foot. Although human infection by VSV has been reported, VSV does not cause any serious symptoms [Fields, B. N., and K. Hawkins. N Engl J Med 277:989, 1967; Johnson, K. M. et al. Am J Trop Med Hyg 15:244, 1966].
VSV is a negative stranded RNA virus which encodes five proteins, nucleocapsid protein (N), phosphoprotein (P), matrix protein (M), surface glycoprotein (G), and RNA dependent RNA polymerase (L). The N, P, and L proteins of VSV are required for synthesis of positive sense and negative sense genomic RNAs and mRNA, which are necessary for the synthesis of VSV proteins, as well as gene of interest such as Human Hepatitis C virus (HCV) proteins.
Since the development of VSV reverse genetics system [Lawson, N. D., et al. Proc Natl Acad Sci USA 92:4477, 1995; Whelan, S. P. et al. Proc Natl Acad Sci USA 92:8388, 1995] to generate recombinant VSVs from cDNA, VSV has been studied as a viral vaccine vector for the immunization of various pathogens [Brandsma, J. L., et al. J Virol 81:5749, 2007; Daddario-DiCaprio, K. M., et al. J Virol 80:9659, 2006; Kohl, W., et al. J Gen Virol 88:157, 2007; Kuate, S., et al. Virology 362:26, 2007; Palin, A., et al. Vaccine 25:741, 2007; Schwartz, J. A., et al. Virology 366:166, 2007].
Although VSV is a rapidly replicating virus, eventually humoral and cellular immune responses against VSV will be elicited in the animal host, like any other viral vectors [Yewdell, J. W. et al. J Exp Med 163:1529-1938, 1986; Puddington, L. et al. J Virol 60:708-717, 1986; Kalinke, U. et al Immunity 5:639-652, 1996]. Animals infected with VSV develop immune responses in one or two weeks including a neutralizing antibody [Kalinke, U. et al Immunity 5:639-652, 1996], which hinders the efficacy of boost immunizations for vaccination with the same vector. VSV is neutralized by serotype specific antibodies against viral surface glycoprotein G. Two different serotypes of VSV, VSV-Indiana (VSVInd) and VSV-New Jersey (VSVNJ) show 50% amino acid identity in the glycoprotein [Gallione, C. J., and Rose, J. K. J. Virol. 46:162-169, 1983]. Antibodies raised against one serotype of VSV do not neutralize the other serotype of VSV [Cartwright, B., and Brown, F. J. Gen. Virol. 16:391-398, 1972]. Therefore, others have used VSVInd as a vaccine vector in which the glycoprotein was replaced with that of VSVNJ to minimize the problems arising from this immune response against the viral vectors [Rose, N. F. et al. J. Virol. 74:10903-10910, 2000; Rose, N. F. et al. Cell 106:539-549, 2001].
Although the VSVInd with G protein of VSVNJ serotype is useful in evading the humoral immune response, it will not prevent the cellular immune response which can be triggered by other VSV proteins including N, P, M, and L proteins. The cellular immune responses against VSV proteins other than the G protein may result in incomplete immune responses against the antigen of interest. Therefore, generation of additional recombinant VSV from another serotype can increase the efficacy of using VSV as a live viral vaccine vector.
Interestingly, it has been previously suggested that generation of a complete rVSVNJ serotype vector was not attempted due to the potential for cross-reactive cytotoxic T-lymphocyte responses between the Indiana and New Jersey serotypes [Clarke et al., Springer Semin Immun 28:239, 2006].
In view of the above background, it would be advantageous to provide an approach for immunoprophylaxis and immunotherapy utilizing both humoral and cellular immune systems. As such, the Applicant has developed a system comprising a combination of vaccines that elicits a response against infectious agents.